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Abstract

Background

We investigated the immunohistochemical expression of p53, MAPK, topoisomerase II
alpha (topoII alpha) and Ki67 in ovarian serous carcinomas (OSCs) along with mutational
analysis for KRAS and BRAF.

Methods

Eighty one cases of OSCs were reviewed and examined immunohistochemically using antibodies
against p53, MAPK, topoII alpha and Ki67. Staining was evaluated as a percentage of
immunopositive cells with cut-off levels at 10% for p53 and topoII alpha, and 5% for
MAPK. The Ki67 immunoexpression was assessed by means of Olympus Image Analysis System
as a percentage of immunopositive cells in 1000 tumor cells. KRAS and BRAF mutational
analysis was performed on 73 available microdissected samples.

Results

Of 81 cases of OSCs 13.6% were of low-grade and 86.4% were of high-grade morphology.
In the high-grade group there was a significantly higher immunoexpression of p53 (P < 0.001) and topoII alpha (P = 0.001), with Ki67 median 56.5 vs. 19 in low-grade group (P < 0.001). The difference in immunoexpression of active MAPK between low- and high-grade
group was also significant (P = 0.003). MAPK positive immunostaining was detected in 63.6% of low-grade vs. 17.1%
of high-grade OSCs. The frequency of KRAS mutation was significantly higher in low-grade
as compared to high-grade group (P = 0.006). None of the samples had BRAF mutation. In addition, we detected positive
MAPK immunoexpression in 13/59 samples with wild-type KRAS, suggesting that activation
of MAPK pathway is not ultimately related either to KRAS or BRAF mutation. Seven morphologically
high-grade samples (11.7%) showed both KRAS mutation and p53 immunopositivity.

Conclusions

Although this study is limited by its humble number of low-grade samples, our data
fit the proposed dualistic pathway of ovarian carcinogenesis. Mutational analysis
for KRAS and BRAF discloses some possible interactions between different tumorigenic
pathways of low- and high-grade carcinomas. Immunohistochemical staining for MAPK
was not sufficiently sensitive, nor specific, to precisely predict the KRAS mutation.
However, it appears to be quite reliable in ruling out a KRAS mutation if the staining
is negative.